Water soluble polymeric prodrugs have been extensively investigated as they can provide site specific drug delivery, longevity in blood circulation, lower drug dosage levels, bicompatibility and biodegradability (R. Duncan, J. Kopecek, Adv. Polym. Sci. 57, 51 (1984), P. Sinko and J. Kohn, "Polymeric Drug Delivery Systems" In: Polymeric Delivery Systems, M. A. El-Nokaly, D. M. Piatt, B. A. Charpentier, Eds. ACS Symposium series 520, American Chemical Society, Washington, D.C., P.18-42 (1993)). Due to immunogenic nature of poly(.alpha. amino acid)s researchers have developed various synthetic polymeric prodrugs as alternatives. These can broadly be classified into two types, 1) bidcompatible prodrugs and 2) biodegradable prodrugs.
Some of the biocompatible polymeric prodrug systems developed are poly (methacrylic acid--co--2(methyl sulfinyl) ethyl methacrylate) (P. Moltz, Int. J Biol. Macromol. 2, 245 (1980)), poly (methacrylic acid--co--N-2 (hydroxypropyl) methacrylamide) and poly (N-vinyl pyrrolidone--co--vinyl amine) (V. Hoffman, H. Ringsdorf, A. Seganova, Macromol. Chem. 180, 837 (1979), R. Duncan, J. Kopecek, P. Rajmanova, J. B. Lloyed, Biochem, Biophys. Acta 755, 518 (1983)). Various drug molecules such as chlorambucil, daunomycin, bis (2 chloroethyl) amine etc. were chemically linked to these polymers and prodrugs so synthesized were evaluated.
Prodrugs based on high molecular weight poly (ethylene glycol)s and poly (oxyethylene dicarboxylic acid)s have also been developed (T. Ouchi, Y. Hagihara, K. Takahashi, Y. Takano, I. Igarashi, Drug Design and Disceovery 9, 93 (1992), R. B. Greenwald, C. W. Gilbert, A. Pendri, C. D. Conover, J. Xia, A. Martinez, J. Med. Chem. 39,424 (1996)).
Although these polymers are biocompatible, they are not biodegradable. Thus, they tend to accumulate in body after the delivery of attached drug molecule (R. Duncan, J. Kopecek Adv. Polym. Sci. 57, 51 (1984). Therefore, biodegradable prodrugs are preferred over biocompatible ones.
Polymers based on low molecular weight poly (ethylene glycol) and various trifunctional amino acids are being investigated as biodegradable prodrugs because the pendant functional groups in such polymers can be used for chemical linkage of drug molecules. Kohn et al (1992) reported water-soluble poly (ether-urethane) based on L-lysine and poly (ethylene glycol). The polymer was synthesize by the reaction of L-lysine ethyl ester with bis (succinimidyl) carbonate derivative poly (ethylene glycol). The polymer so synthesized was treated with sodium hydroxide in order to de-block the side chain carboxyl groups of L-lysine and make them available for drug linkage. (A. Nathan, D. Bolika, N. Vyavahare, S. Zalipsky, J. Kohn, Macromolecules 25, 4476 (1992)). Ulbrich et al (1997) reported a prodrug system based on poly (oxyethylene glycol) and L-glutanic acid. This polymer was synthesized by connecting two blocks of monomethoxy poly (oxyethylene) carboxylic acid via biodegradable oligopeptide-1,4 bis (.gamma.-para-nitroanilido glutamido) ethylene diamide (M. Pechar, J. Strohalm, K. Ulbrich, Macromol. Chem. 198, 1009 (1997)). The oligopeptide was synthesized following standard procedures of blocking and de-blocking of --NH.sub.2 and --COOH groups of amino acid. Won et al (1998) reported a polymer based on poly (ethylene glycol) and L-aspartic acid. In this, N-benzyloxylcarbonyl L-aspartic acid (N-cbz-L-aspartic acid) was converted into N-cbz-aspartic anhydride by the reaction of thionyl chloride. Subsequently, N-cbz-aspartic anhydride was reacted with poly (ethylene glycol) to obtain a polymer with blocked --NH.sub.2 groups. This polymer was treated with 1,4 cyclohexadiene and Palladium/activated charcoal in order to de-block --NH.sub.2 groups and make them available for drug linkage (C-Y Won, C-C chu J. D. Lee, J. Polym. Sci. Chem. Ed. 36, 2949 (1998).
Thus, due to such tedious blocking and de-blocking procedures of --NH.sub.2 and --COOH groups, a very few examples (mentioned herein above) of prodrugs based on trifunctional amino acids and poly (ethylene glycol) are reported so far.